Abstract Following ischemic renal injury (IRI), selective proximal straight tubule (PST) injury occurs in in vivo experimental models. Previous reports indicated that selective glycolytic inhibition and the consequent ATP depletion is the initiating cause that triggers all the subsequent events leading to PST injury and cell death to instigate renal dysfunction; however, the exact mechanism by which glycolysis is inhibited is not elucidated. Our recent report demonstrates that poly (ADP-ribose) Polymerase-1 (PARP-1) mediated inhibition of the key glycolytic enzyme, glyceraldehyde-3- phosphate dehydrogenase (GAPDH), can induce downregulation of glycolysis and ATP depletion in IRI. However, GAPDH inhibition by PARP-1 only partially accounted for ATP depletion, suggesting that synergetic inhibition at additional glycolytic steps may occur. The current proposal is based on new preliminary data indicating a novel paradigm that links p53 target TIGAR (Tp53 inducible glycolysis and apoptosis regulator) to metabolic regulation of the rate limiting glycolytic enzyme Phosphofructokinase (PFK) to induce ATP depletion and PST injury post-IRI. The objective of the proposal is to define the role and the mechanisms by which TIGAR regulate glycolytic energy metabolism in ischemic renal PST and determine whether synergistic inhibition of TIGAR and PARP- 1 protects from glycolytic inhibition and ATP depletion in the setting of IRI. The central hypothesis is that modulation of the activity of the key glycolytic enzymes, PFK and GAPDH by TIGAR and PARP-1 respectively, leads to downregulation of glycolysis and anaerobic ATP production in ischemic PSTs. Based on our strong preliminary data, the validity of the hypothesis will be tested by pursuing the following three specific aims: 1) determine the mechanism by which TIGAR activation in renal PSTs inhibits anaerobic energy production post-IRI; 2) determine if the level of ischemic stress switch TIGAR response towards ROS scavenging and autophagy versus glycolytic inhibition and cell death pathways post-IRI and 3) determine if synergetic inhibition of TIGAR and PARP activation completely protects PST from ischemic/hypoxic injury in in vivo models. Successful completion of the proposed studies, will establish a new paradigm on the role of PARP-1 and TIGAR as the primary mechanism that initiates glycolytic inhibition, ATP depletion and PST injury in IRI. The studies are innovative as a role for PARP-1 and TIGAR in glycolytic inhibition in a pathological condition such as ischemia/reperfusion injury has not been previously addressed in any organ. Results from the study may provide novel therapeutic opportunities to intervene in PARP-1 and TIGAR functions to modulate PST injury at its onset and may be extrapolated to intervene in the pathogenesis of human AKI.